Composition of dialysis liquid comprising crystallisation inhibitor substances

ABSTRACT

This invention relates to a composition that comprises inositol phosphates and/or bisphosphonates, and to the use thereof to prevent the loss of substances of biological interest in the body of patients subjected to dialysis and to maintain sufficient physiological levels of said substances to regulate physiological and/or pathological processes, these substances being inhibitors of pathological crystallisation.

This invention relates to a composition that comprises inositolphosphates and/or bisphosphonates, and to the use thereof to prevent theloss of substances of biological interest in the body of patientssubjected to dialysis and maintain sufficient physiological levels ofsaid substances to regulate physiological and/or pathological processes,these substances being inhibitors of pathological crystallisation.

PRIOR STATE OF THE ART

Acute renal dysfunction consists of a rapid decrease in the excretoryrenal function. Patients who suffer from this condition are treated withdifferent therapeutic alternatives, which include haemodialysis andperitoneal dialysis.

Due to the lack of excretory function in renal failure processes, thereis an accumulation of metabolic waste products. When the kidneys areincapable of performing their function, patients need to be subjected todialysis processes or kidney transplantation in order to survive.

Dialysis is one of the alternatives used as a treatment for thisalteration and involves the use of a semi-permeable membrane thatseparates the blood from another liquid called dialysing liquid ordialysis liquid.

In haemodialysis, an artificial kidney, the most important part whereofis the dialyser, is used. The latter is composed of a compartment forthe blood and another compartment for the dialysis liquid, both fluidsalways circulating in opposite directions in order to make the maximumutilisation of diffusion in favour of the solute concentration gradient.Both compartments are separated by a semi-permeable membrane that,basically, may be of 4 different types:

-   -   Cellulose membrane (Cuprofan): it is the most widely used. It is        composed of chains of glucose rings with numerous free hydroxyl        groups.    -   Substituted cellulose membranes: they are obtained by means of a        chemical bond between a large number of free hydroxyl radicals        and acetate. Also called cellulose acetate.    -   Cellulosynthetic membranes: modification by the addition of a        synthetic material, such as diethylaminoethyl in the production        of Hemophan.    -   Synthetic membranes: they do not contain cellulose and are more        permeable and more biocompatible than cellulose membranes. The        varieties of this type of membranes include polyacrylonitrile,        polysulfone, polyamide or polymethylmethacrylate.

In peritoneal dialysis, the operating scheme is analogous to that ofhaemodialysis, although the semi-permeable membrane used is theperitoneal mesothelium that coats the inner surface of the abdominalcavity and the organs inside it. Thus, the dialysis liquid is introducedinto the peritoneal cavity, whereas the compartment for the blood is thelumen of the capillaries that irrigate the peritoneal mesothelium.

The composition of the dialysis liquid is such that, by means of adiffusion process, it makes it possible to eliminate waste substancesfrom the blood and, additionally, makes it possible to regulate thevolume of water and the electrolytic concentration thereof, due to itscontrolled composition of ions, such as, for example, sodium, potassium,chloride, magnesium or calcium.

This liquid also has a high glucose concentration (which makes itpossible for it to achieve an isotonic osmolality with that of plasma)and is buffered with an acetate or bicarbonate buffer.

However, blood has naturally existing substances that are not present inthe dialysis liquid, but which, nonetheless, are of biological interest.These substances undergo a clearance process when a dialysis process isperformed using a semi-permeable membrane (Van der Kaay J., Van HaastertP. J. M., Analytical Biochemistry 1999; 225: 183-185). Moreover, thisclearance process may eliminate up to 100% of the substance, apercentage that may be modified as a function of the medium's ionicstrength.

DESCRIPTION OF THE INVENTION

There is a need to maintain effective physiological concentrations ofcertain substances that may contribute to regulate physiological and/orpathological crystallisation and calcification processes.

Specifically, it is necessary to improve the composition of dialysisliquids in order that, following the dialysis process whereto thosepatients needing it are subjected, the concentration of some biologicalsubstances in blood serum does not substantially decrease or tointroduce certain substances in the dialysing liquid in order for theplasma concentration thereof following dialysis is adequate.Alternatively, given the modification of the concentration of saidsubstances during the dialysis process, the plasma concentration thereofmay be once again regulated by the administration of an intravenousformulation. The levels of said substances may be regulated byintravenous administration before, during or after the dialysis processwhereto the patients are subjected.

Therefore, this invention relates to the introduction of substances ofbiological interest, for example, in dialysis liquid compositions and/orintravenous formulations and to the use thereof in order to prevent theloss of said substances from the blood, maintain adequate plasma levelsor increase plasma levels to physiologically adequate values.

The interest of these substances and similar compounds for dialysedpatients is particularly relevant if we take into consideration thatrenal failure leads to situations of hyperphosphataemia, which increasesthe oversaturation of calcium phosphate in the urine, and, therefore,may cause pathological cardiovascular calcification processes.

The objective of this invention is to introduce substances with anactivity as crystallisation inhibitors in dialysis liquid compositionsand/or intravenous formulations. Specifically, the purpose is tointroduce inositol phosphates, more specifically phytate, and/orbisphosphonates into dialysis liquid compositions, and inositolphosphates, phytate amongst them, into intravenous formulations.

Specifically, this invention relates to dialysis liquid compositions andintravenous formulations that contain substances with an activity ascrystallisation inhibitors. More particularly, these substances areinositol phosphates, preferably phytate, and/or bisphosphonates.

Bisphosphonates are synthetic compounds which are resistant to theenzymatic hydrolysis of phosphatases and, therefore, the exogenoussupply thereof by oral route is more effective than that ofpyrophosphate. Although the use thereof as drugs focuses on thetreatment of bone resorption processes, they also have properties asinhibitors of the crystallisation of calcium salts. On the other hand,phytate, or myo-inositol hexaphosphate, is a molecule with outstandingproperties as an inhibitor of the crystallisation of calcium salts,since it has 6 phosphate groups and, therefore, a high affinity fordivalent ions such as calcium. Thus, preventive properties relative tothe development of pathological calcifications, such as renal lithiasisor cardiovascular calcifications, have been described.

The introduction of substances into dialysis liquid compositions mayprevent the loss thereof from the blood, maintain adequate plasma levelsor increase the plasma levels thereof to physiologically adequatevalues. Alternatively, given the modification of the concentration ofsaid substances during the dialysis process, the plasma concentrationmay once again be regulated by the administration of an intravenousformulation before, during or after the dialysis process.

In this invention, “crystallisation inhibitor” is understood to mean asubstance that is capable of preventing, curbing or decreasingcrystallisation in any of the stages thereof, whether nucleation,crystalline growth or aggregation.

In this invention, “dialysis liquid” or “dialysing liquid” is understoodto mean an electrolytic solution similar to that of blood plasma whichdoes not contain the waste substances that accumulate in the body in thecase of renal failure. Said solution is used in dialysis processes inorder to reduce the accumulation of metabolic waste products, regulatethe plasma volume and regulate the concentration of electrolytes in theblood.

Those skilled in the art know that one of the key elements of thedialysis process is the dialysing membrane, which is a part of theartificial kidney, in the case of haemodialysis, and the peritonealmesothelium, in the case of peritoneal dialysis. In both cases, the poresize of the membrane prevents the loss of macromolecules such asproteins during the dialysis process, but allows for the exchange ofelectrolytes and low-molecular-weight substances. Thus, suitablequantities of ions such as sodium, potassium, chloride, magnesium orcalcium are introduced into the dialysis liquids used in order tomaintain adequate plasma levels.

However, there are no descriptions of the incorporation of inositolphosphates and/or bisphosphonates into said dialysing liquidcompositions, which would allow to prevent a reduction in the plasmaconcentration thereof during the dialysis process (due to theconcentration gradient between the blood and the dialysing liquid thatallows for diffusion and, therefore, the clearance of these substances)or maintain/increase the plasma concentration thereof following thedialysis process (FIGS. 1-4). In general, they are low-molecular-weightsubstances which, therefore, cross the pores of the semi-permeablemembranes used in dialysis. Moreover, as an alternative to the methoddescribed above, the modification of the plasma concentration ofinositol phosphates in patients may be corrected by the administrationof an intravenous formulation.

These substances may be of natural origin, as in the case of phytate andother inositol phosphates, but synthetic substances that exert a similarfunction, as in the case of bisphosphonates, may also be introduced intothe composition.

Therefore, a first aspect of this invention relates to a compositionthat comprises crystallisation inhibitory substances selected from thelist that comprises inositol phosphate, bisphosphonate, thepharmaceutically acceptable salts or any of the combinations thereof, tobe used in the preparation of a dialysis liquid.

Inositol phosphate may contain between 1 and 6 phosphate groups(inositol mono-, di-, tri-, tetra-, penta- and hexa-phosphate). In apreferred embodiment, the crystallisation inhibitory substance isinositol phosphate containing between 1 and 6 phosphate groups, morepreferably, inositol hexaphosphate (also called phytic acid or phytate)and, even more preferably, myo-inositol hexaphosphate.

In a preferred embodiment, the crystallisation inhibitory substance isbisphosphonate, which is selected from the list that comprises etidronicacid, alendronic acid, risedronic acid, zoledronic acid, tiludronicacid, pamidronic acid, clodronic acid, ibandronic acid, the salts or anyof the combinations thereof.

A preferred embodiment of the dialysis liquid or the intravenousformulation of the invention additionally comprises other compounds,such as, for example, without being limited thereto, pyrophosphateand/or any of the pharmaceutically acceptable salts thereof.

The concentration of these substances in the dialysis liquid and/or theintravenous formulation will be dependent on several factors, such asthe composition of the dialysis liquid, the dialysis time, the severityof the renal dysfunction, etc. In this invention, stable dialysis liquidcompositions have been made wherein the quantity of inositol phosphateand/or bisphosphonate ranges between 0.1 μM and 0.1 M. Preferably, theconcentration of inositol phosphate and/or bisphosphonate ranges between0.1 μM and 10 mM; more preferably, between 0.1 μM and 1 mM.

An example of a dialysis liquid composition (for both peritonealdialysis and haemodialysis) whereto this type of substances could beadded would be composed of glucose, sodium, potassium, chlorine,calcium, magnesium, buffer (primarily, without being limited thereto,bicarbonate or acetate), etc. On the other hand, the high glucoseconcentration makes it possible to regulate the osmolality such that itis isotonic with the plasma. In addition, dextrose, lactate, heparin,antibiotics or auxiliary compounds that perform a specific function maybe introduced into the plasma.

Another aspect of this invention relates to a dialysis liquid thatcomprises crystallisation inhibitory substances selected from the listthat comprises inositol phosphate, bisphosphonate, the pharmaceuticallyacceptable salts or any of the combinations thereof, and to the usethereof for both haemodialysis and peritoneal dialysis. This compositionthat contains a crystallisation inhibitory substance is used tomaintain, increase or prevent a decrease in the plasma concentration ofsaid inhibitory substance.

The composition of the invention may be incorporated into a dialysisliquid formulation or a formulation adapted for intravenousadministration.

Therefore, another aspect of this invention relates to a compositionthat comprises inositol phosphate and/or any of the salts thereof in aform adapted for intravenous administration to be used in the treatmentor prevention of pathological processes associated with thede-regulation of the physiologically adequate levels of said substancesin the blood plasma. The treatment or prevention of de-regularisation isperformed by maintaining or increasing the levels of said substances inthe patients' plasma.

The pathological processes associated with the de-regularisation of thephysiologically adequate levels of said substances in the blood plasmaare of a very diverse nature, and may refer, without being limitedthereto, to any pathology associated with calcium disorders, such as,for example, renal lithiasis, cardiovascular calcification, calcinosiscutis, osteoporosis or calcium podagra. On the other hand, this disorderor de-regularisation is also related to oncology, specifically, somecancers, such as colon, bone or skin cancer.

In the case of the intravenous formulations, stable compositions havebeen prepared wherein the quantity of inositol phosphate to beadministered ranges between 1 nmol/kg and 0.1 mol/kg (with respect tothe weight of the subject receiving the formulation). Preferably, theconcentration of inositol phosphate ranges between 0.01 μmol/kg and 10mmol/kg; more preferably, between 0.1 μmol/kg and 1 mmol/kg.

The crystallisation inhibitory substance is preferably inositolphosphate containing between 1 and 6 phosphate groups, more preferably,inositol hexaphosphate and, even more preferably, myo-inositolhexaphosphate. Said composition may additionally comprise pyrophosphate.

An example of an intravenous formulation contains inositol phosphate,and could additionally contain sodium, chlorine, buffer and/or otherexcipients, vehicles and inhibitory substances such as bisphosphonatesor pyrophosphate. In this invention, “intravenous administration” isunderstood to include both injectable or direct administration, that is,the administration of the composition in the form of a bolus, whetheralone or diluted, or intravenous infusion, where the composition isadded through a venous channel, by intravenous drip.

On the other hand, another aspect of the invention relates to a combinedpreparation that comprises, at least, the composition of the inventionand a dialysis liquid to be used separately, simultaneously orsequentially in the treatment or prevention of the regulation of thephysiologically adequate levels of the inhibitory substances,maintaining or, increasing these levels, in the plasma of patientssubjected to dialysis.

In a preferred embodiment, the composition of the invention used in thecombined preparation is in a form adapted to intravenous administration.

Throughout the description and the claims, the word “comprises” and thevariants thereof are not intended to exclude other technicalcharacteristics, additives, components or steps. For those skilled inthe art, other objects, advantages and characteristics of the inventionwill arise partly from the description and partly from the practise ofthe invention. The following examples and drawings are provided forillustrative purposes, and are not intended to limit the scope of thisinvention.

DESCRIPTION OF THE FIGURES

FIG. 1 shows that up to 40% of the phytate in an artificial blood plasmasample, during a dialysis process using a dialysis liquid withoutphytate, is lost by clearance in 20 hours.

FIG. 2 shows that the phytate in an artificial blood plasma sample,during a dialysis process using a dialysis liquid with a phytateconcentration greater than that of the plasma, makes it possible toincrease the plasma concentration throughout a 20-hour period.

FIG. 3 shows that up to 95.6% of the etidronate in an artificial bloodplasma sample, during a dialysis process using a dialysis liquid withoutetidronate, is lost by clearance in 20 hours.

FIG. 4 shows that the etidronate in an artificial blood plasma sample,during a dialysis process using a dialysis liquid with a concentrationof etidronate greater than that of the plasma, makes it possible toincrease the plasma concentration throughout a 20-hour period.

EXAMPLES

Below we will illustrate the invention by means of assays performed bythe inventors, which show the specificity and effectiveness of thecomposition of the invention administered in the form of an injection,intravenous infusion or dialysis liquid.

Example 1

An artificial plasma (liquid with a composition similar to that ofplasma) was prepared with 1.5 mM phytate, regulating the ionic strengthwith 0.15 NaCl. 25 ml of this solution were dialysed for 20 hoursagainst a 1-l volume of a 0.15 M NaCl solution without phytate(dialysing liquid model). The pH of both solutions was adjusted to 7.4using bicarbonate buffer.

5-ml aliquots of the dialysing liquid were collected at times 0, 1, 3, 6and 20 hours, and the quantity of phytate in each of them wasdetermined. Moreover, the concentration of phytate in the artificialplasma was determined at times 0 and 20 hours.

The concentration of phytate in the artificial plasma after 20 hours ofdialysis was 40% lower than the initial concentration. FIG. 1 showsthat, during the dialysis process, clearance of the phytate takes place,increasing the quantity of phytate in the dialysis solution until 40% ofthe initial quantity in the artificial plasma is reached, after a20-hour period.

Example 2

An artificial plasma was prepared with 1.5 mM of phytate, regulating theionic strength with 0.15 M NaCl. 25 ml of this solution were dialysedfor 20 hours against a 1-l volume of a 0.15 M NaCl solution with thesame concentration of phytate as the plasma. The pH of both solutionswas adjusted to 7.4 using bicarbonate buffer.

5-ml aliquots of the dialysing liquid were collected at times 0, 1, 3, 6and 20 hours, and the quantity of phytate was determined in each ofthem. Moreover, the concentration of phytate in the artificial plasmawas determined at times 0 and 20 hours.

During the dialysis process, there are no variations in theconcentration of phytate, either in the plasma or the dialysing liquid;therefore, the introduction of phytate into the dialysing liquidprevents the loss of this substance in the blood.

Example 3

An artificial plasma was prepared with 300 μM of phytate, regulating theionic strength with 0.15 M NaCl. 25 ml of this solution were dialysedfor 20 hours against a 1-l volume of a 0.15 M NaCl solution with aconcentration of phytate 5 times greater than that of the plasma. The pHof both solutions was adjusted to 7.4 using bicarbonate buffer.

5-ml aliquots of the dialysing liquid were collected at times 0, 1, 3, 6and 20 hours, and the quantity of phytate was determined in each ofthem.

Moreover, the concentration of phytate in the artificial plasma wasdetermined at times 0 and 20 hours.

The results are shown in FIG. 2. It may be observed that, during thedialysis process, up to 0.75% of the phytate from the dialysis liquidenters into the artificial plasma; therefore, taking into considerationthe ratio of initial volumes and concentrations, the concentration ofphytate in the artificial plasma has increased by 140%; consequently, itis possible to re-establish normal values of phytate by introducing itinto the dialysis liquid.

Example 4

An artificial plasma was prepared with 5 mM of etidronate, regulatingthe ionic strength with 0.15 M NaCl. 25 ml of this solution weredialysed for 20 hours against a 1-l volume of a 0.15 M NaCl solutionwithout etidronate (dialysing liquid model). The pH of both solutionswas adjusted to 7.4 using bicarbonate buffer.

5-ml aliquots of the dialysing liquid were collected at times 0, 1, 3, 6and 20 hours, and the quantity of etidronate was determined in each ofthem. Moreover, the concentration of etidronate in the artificial plasmawas determined at times 0 and 20 hours.

The concentration of etidronate in the artificial plasma after 20 hoursof dialysis was 95.6% lower than the initial concentration. In FIG. 3,it may be observed that, during the dialysis process, clearance of theetidronate takes place, increasing the quantity of etidronate in thedialysis solution to reach 95.6% of the initial quantity in theartificial plasma, after a 20-hour period.

Example 5

An artificial plasma was prepared with 5 mM of etidronate, regulatingthe ionic strength with 0.15 M NaCl. 25 ml of this solution weredialysed for 20 hours against a 1-l volume of a 0.15 M NaCl solutionwith the same concentration of etidronate as the plasma. The pH of bothsolutions was adjusted to 7.4 using bicarbonate buffer.

5-ml aliquots of the dialysing liquid were collected at times 0, 1, 3, 6and 20 hours, and the quantity of etidronate was determined in each ofthem. Moreover, the concentration of etidronate in the artificial plasmawas determined at times 0 and 20 hours.

During the dialysis process, there are no variations in theconcentration of etidronate, either in the plasma or the dialysingliquid; therefore, the introduction of etidronate in the dialysingliquid prevents the loss of this substance in the blood.

Example 6

An artificial plasma was prepared with 1 mM of etidronate, regulatingthe ionic strength with 0.15 M NaCl. 25 ml of this solution weredialysed for 20 hours against a 1-l volume of a 0.15 M NaCl solutionwith a concentration of etidronate 5 times greater than that of theplasma. The pH of both solutions was adjusted to 7.4 using bicarbonatebuffer.

5-ml aliquots of the dialysing liquid were collected at times 0, 1, 3, 6and 20 hours, and the quantity of etidronate was determined in each ofthem. Moreover, the concentration of etidronate in the artificial plasmawas determined at times 0 and 20 hours.

The results are shown in FIG. 4. It may be observed that, during thedialysis process, up to 1.65% of the etidronate from the dialysis liquidenters into the artificial plasma; therefore, taking into considerationthe ratio of initial volumes and concentrations, the concentration ofetidronate in the artificial plasma has increased by 330%; consequently,it is possible to increase the plasma levels of etidronate byintroducing it into the dialysis liquid.

Example 7

Dialysis liquid compositions (for both haemodialysis and peritonealdialysis) whereto inositol phosphate and/or bisphosphonates are added:

Compound Composition 1 Composition 2 Inositol phosphate 0.1 μM-0.1Mand/or bisphosphonate glucose 200 mg/dl  250 mg/dl  sodium 136 mEq/l 146 mEq/l potassium  0 mEq/l  3 mEq/l chlorine  96 mEq/l 115 mEq/lcalcium 2.5 mEq/l 3.25 mEq/l  magnesium 0.5 mEq/l  1.5 mEq/l buffer  35mEq/l  40 mEq/l

The high glucose concentration makes it possible to regulate theosmolality so that it is isotonic with the plasma. Moreover, dextrose,heparin, lactate, antibiotics and auxiliary compounds that perform aspecific function may be introduced into the plasma.

Example 8

Compositions of formulations designed for intravenous administration inpatients subjected to various medical procedures (both treatments byinjection or intravenous infusion and haemodialysis or peritonealdialysis), whereto inositol phosphates, including phytate, are added.The concentration of inositol phosphate is adjusted as a function of thevolume of intravenous administration to obtain the quantities specifiedin the table.

Compound Composition 1 Composition 2 Inositol phosphate 1nmol/kg/day-0.1 mol/kg/day M sodium — 1146 mEq/l chlorine —  115 mEq/l

Moreover, auxiliary compounds that perform a specific function may beintroduced.

Example 9

6 male Wistar rats approximately 250 g in weight were acclimated fro 7dias in the animal house (T=1±1° C. and humidity=60±5%) with 12:12-hourlight-darkness cycles. The rats were housed in Plexiglas cages, with oneanimal per cage, and fed with food and drink ad libitum.

Following the acclimation period, the animals were randomly divided intotwo groups with 3 rats each, a control group (with a diet withoutphytate, thereby simulating a post-dialysis physiological condition) anda treated group, which received 3 intravenous doses of 0.61 mmol/kg (400μg/kg) separated by 12-hour periods. Following the last administration,24-hour urine samples were collected in order to determine the phytateand, subsequently, the animals were anaesthesised and blood samples werecollected.

The procedures used in this experiment were performed in accordance withDirective 86/609/EEC regarding the protection of animals used forexperimental and scientific purposes.

The urinary excretions of phytate at the end of the study werestatistically lower in the control group (4.0+/−1.5 □g) as compared tothe treated group (72+/−10 μg). Upon comparing the plasma levels, avalue of 0.013+/−0.006 mg/l was obtained for the control group and of1.0+/−0.2 mg/l for the treated group; therefore, it was demonstrated forthe first time that the administration of an intravenous formulationunder conditions of plasma depletion of inositol phosphates is capableof correcting said deficient levels, achieving much higher plasma levelsthan may be achieved by means of oral administration, surprisingly even24 hours after the intravenous administration thereof.

1. Composition that comprises crystallisation inhibitory substancesselected from the list that comprises inositol phosphate,bisphosphonate, the pharmaceutically acceptable salts or any of thecombinations thereof, to be used in the preparation of a dialysisliquid.
 2. Composition as claimed in claim 1, where the crystallisationinhibitory substance is the inositol phosphate that contains between 1and 6 phosphate groups.
 3. Composition as claimed in claim 2, where theinositol phosphate is inositol hexaphosphate.
 4. Composition as claimedin claim 3, where the inositol phosphate is myo-inositol hexaphosphate.5. Composition as claimed in claim 1, where the bisphosphonate isselected from the list that comprises etidronic acid, alendronic acid,risedronic acid, zoledronic acid, tiludronic acid, pamidronic acid,clodronic acid, ibandronic acid, the salts or any of the combinationsthereof.
 6. Composition as claimed in any of claims 1 to 5, whichadditionally comprises pyrophosphate.
 7. Composition as claimed in anyof claims 1 to 6, where the crystallisation inhibitory substances are ina concentration of between 0.01 μM and 0.1 M.
 8. Composition as claimedin claim 7, where the crystallisation inhibitory substances are in aconcentration of between 0.1 μM and 10 mM.
 9. Composition as claimed inclaim 8, where the crystallisation inhibitory substances are in aconcentration of between 0.1 μM and 5 mM.
 10. Dialysis liquid thatcomprises crystallisation inhibitory substances selected from the listthat comprises inositol phosphate, bisphosphonate, the pharmaceuticallyacceptable salts or any of the combinations thereof.
 11. Use of thedialysis liquid as claimed in claim 10, for haemodialysis or peritonealdialysis.
 12. Composition that comprises inositol phosphate and/or anyof the salts thereof in a form adapted for intravenous administration,to be used in the treatment or prevention of pathological processesassociated with the de-regularisation of the physiologically adequatelevels of said substances in the blood plasma.
 13. Composition asclaimed in claim 12, where the inositol phosphate contains between 1 and6 phosphate groups.
 14. Composition as claimed in claim 13, where theinositol phosphate is inositol hexaphosphate.
 15. Composition as claimedin claim 14, where the inositol phosphate is myo-inositol hexaphosphate.16. Composition as claimed in any of claims 12 to 15, where the dose ofinositol phosphate and/or any of the pharmaceutically acceptable saltsthereof is between 1 nmol/kg and 0.1 mol/kg.
 17. Composition as claimedin any of claims 12 to 16, which additionally comprises pyrophosphate.18. Composition as claimed in any of claims 12 to 17, where thetreatment or prevention of de-regularisation is performed by maintainingof increasing the levels of said substances in the plasma of a personsubjected to dialysis.
 19. Combined preparation that comprises, atleast, a composition that comprises crystallisation inhibitorysubstances selected from the list that comprises inositol phosphate,bisphosphonate, the pharmaceutically acceptable salts or any of thecombinations thereof, and a dialysis liquid to be used separately,simultaneously or sequentially in the treatment or prevention ofpathological processes associated with the de-regularisation of thephysiologically adequate levels of said substances in the plasma ofpatients subjected to dialysis.
 20. Combined preparation as claimed inclaim 19, where the composition is in a form adapted for intravenousadministration.